Chemical transformation of xenobiotics by the human gut microbiota.
Chemical transformation of xenobiotics by the human gut microbiota.
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DOI：
10.1126/science.aag2770
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发表时间：
2017-06-23
期刊：
影响因子：
--
通讯作者：
Balskus EP
中科院分区：
文献类型：
--
作者：
Koppel N;Maini Rekdal V;Balskus EP
人体肠道微生物区系对摄入的化合物(外来生物物质)的新陈代谢做出了关键贡献，将数百种饮食成分、工业化学品和药物转化为体内活动、毒性和寿命发生变化的代谢物。肠道微生物异源代谢的化学成分通常与宿主酶的化学成分不同。尽管它们对人类生物学产生了重要的影响，但参与异物代谢的肠道微生物、基因和酶却知之甚少。将这些微生物转化与酶联系起来并阐明它们的生物学效应无疑是具有挑战性的。然而，最近的研究表明，将传统技术和新兴技术相结合可以使这一目标取得进展。最终，对肠道微生物异种代谢的分子理解将指导个性化的药物和营养，为毒理学风险评估提供信息，并改进药物的发现和开发。人类摄取了大量与身体无关的小分子(异生物质)，包括饮食成分、环境化学品和药物。生活在我们胃肠道(人体肠道微生物区系)中的数以万亿计的微生物可以直接改变这些化合物的化学结构，从而改变它们的寿命、生物利用度和生物效应。我们对外来生物的肠道微生物转化如何影响人类健康的了解还处于初级阶段，考虑到肠道微生物区系的重要性，这是令人惊讶的。我们目前缺乏对这种新陈代谢在个体之间的差异程度、这些微生物活动影响人类生物学的机制以及我们如何合理地操纵这些反应的了解。这种缺陷很大程度上源于难以将这种微生物化学物质与特定的生物体、基因和酶联系起来。在过去的几十年里，对肠道微生物区系介导的外源生物修饰的研究表明，这些生物集体拥有比人类细胞更大的代谢谱。人类和微生物对摄入化合物的转化之间的化学差异不仅源于这个复杂和可变的群落中存在的酶的多样性，而且还源于塑造这些活动的不同的选择压力。例如，虽然宿主代谢的进化促进了许多外来物质从体内排泄，但这些化合物及其人类代谢物的微生物修饰往往通过提供营养或产生能量来支持微生物的生长。值得注意的是，微生物转化的化学往往与宿主代谢的化学相反或相反，改变了外源化合物和相关代谢物的药代动力学和药效学性质。受肠道微生物代谢影响的外源生物的范围令人印象深刻，而且还在不断扩大。肠道微生物可以改变许多种类的饮食化合物，包括复杂的多糖、脂类、蛋白质和植物化学物质。这些代谢反应与多种健康益处以及疾病易感性有关。肠道微生物也能够转化工业化学品和污染物，改变它们在体内的毒性和寿命。同样，药物的微生物转化可以改变它们的药代动力学性质，对前药激活至关重要，并导致不良副作用或疗效丧失。在绝大多数情况下，调节这些反应的单个微生物和酶是未知的。人体肠道微生物代谢外源物质。生活在人体肠道中的微生物会改变摄入化合物的化学结构，包括饮食成分、工业化学品和药物。这些变化会影响外来生物的毒性、生物活性和生物利用度。gutmicrobialenzymesresponsibleformanyofthesetransformationsarepoorlyunderstood.Me，甲基。在强调微生物异种代谢与人类健康相关性的发现的推动下，科学家们越来越多地寻求发现和操纵这些转化所涉及的酶化学。最近探索肠道微生物如何代谢药物地高辛和伊立替康以及饮食营养胆碱的工作，为此类研究提供了指导。这些研究结合了传统方法和现代方法，说明了对肠道微生物异生代谢的分子理解如何能够指导以假说为导向的研究，了解这些反应在微生物区系和宿主生物学中所起的作用。在了解肠道微生物区系对异生代谢的贡献方面，我们仍然面临着无数的挑战。我们必须将许多已知的微生物转化与负责这些活动的基因和酶联系起来，酶机制和生化逻辑的知识将有助于实现这一目标。还有很大的需要去发现目前与这个社区相关的未被赏识的活动。全面揭示肠道中微生物介导的转化可能会给我们带来新的视角，让我们了解关于饮食、污染物和药物对人类健康的影响的许多变量和相互矛盾的研究。微生物基因和酶将提供操纵的特定目标和诊断标记，可纳入临床研究和实践。最终，对肠道微生物异种代谢的分子理解将为个性化营养、毒理学风险评估、精确医学和药物开发提供信息。
The human gut microbiota makes key contributions to the metabolism of ingested compounds (xenobiotics), transforming hundreds of dietary components, industrial chemicals, and pharmaceuticals into metabolites with altered activities, toxicities, and lifetimes within the body. The chemistry of gut microbial xenobiotic metabolism is often distinct from that of host enzymes. Despite their important consequences for human biology, the gut microbes, genes, and enzymes involved in xenobiotic metabolism are poorly understood. Linking these microbial transformations to enzymes and elucidating their biological effects is undoubtedly challenging. However, recent studies demonstrate that integrating traditional and emerging technologies can enable progress toward this goal. Ultimately, a molecular understanding of gut microbial xenobiotic metabolism will guide personalized medicine and nutrition, inform toxicology risk assessment, and improve drug discovery and development. Humans ingest a multitude of smallmolecules that are foreign to the body (xenobiotics), including dietary components, environmental chemicals, and pharmaceuticals. The trillions of microorganisms that inhabit our gastrointestinal tract (the human gut microbiota) can directly alter the chemical structures of such compounds, thus modifying their lifetimes, bioavailabilities, and biological effects. Our knowledge of how gut microbial transformations of xenobiotics affect human health is in its infancy, which is surprising given the importance of the gut microbiota. We currently lack an understanding of the extent to which this metabolism varies between individuals, the mechanisms by which these microbial activities influence human biology, and how we might rationally manipulate these reactions. This deficiency stems largely from the difficulty of connecting this microbial chemistry to specific organisms, genes, and enzymes. Over the past several decades, studies of gut microbiota–mediated modification of xenobiotics have revealed that these organisms collectively have a larger metabolic repertoire than human cells. The chemical differences between human andmicrobial transformations of ingested compounds arise not only from the increased diversity of enzymes present in this complex and variable community but also from the distinct selection pressures that have shaped these activities. For example, whereas host metabolism evolved to facilitate excretion of many xenobiotics from the body, microbial modifications of these compounds and their human metabolites often support microbial growth through provision of nutrients or production of energy. Notably, the chemistry of microbial transformations often opposes or reverses that of host metabolism, altering the pharmacokinetic and pharmacodynamic properties of xenobiotics and associated metabolites. The range of xenobiotics subject to gutmicrobial metabolism is impressive and expanding. Gut microbes modify many classes of dietary compounds, including complex polysaccharides, lipids, proteins, and phytochemicals. These metabolic reactions are linked to a variety of health benefits, aswell as disease susceptibilities. Gut microbes are also able to transform industrial chemicals and pollutants, altering their toxicities and lifetimes in the body. Similarly, microbial transformations of drugs can change their pharmacokinetic properties, be critical for prodrug activation, and lead to undesirable side effects or loss of efficacy. In the vast majority of cases, the individual microbes and enzymes that mediate these reactions are unknown. Human gut microbes metabolize xenobiotics. Themicroorganisms that inhabit the human gut alter the chemical structures of ingested compounds, including dietarycomponents, industrial chemicals, and drugs.These changes affect xenobiotic toxicity, biological activity, and bioavailability.The gutmicrobialenzymesresponsibleformanyofthesetransformationsarepoorlyunderstood.Me,methyl. Fueled by findings underscoring the relevance of microbial xenobiotic metabolism to human health, scientists are increasingly seeking to discover and manipulate the enzymatic chemistry involved in these transformations. Recent work exploring how gut microbes metabolize the drugs digoxin and irinotecan, as well as the dietary nutrient choline, provides guidance for such investigations. These studies, which combine traditional methods with modern approaches, illustrate how a molecular understanding of gut microbial xenobiotic metabolism can guide hypothesis-driven research into the roles these reactions play in both microbiota and host biology. We still face a myriad of challenges in understanding the gut microbiota’s contribution to xenobiotic metabolism. It is imperative that we connect the many known microbial transformations with the genes and enzymes responsible for these activities, and knowledge of enzyme mechanism and biochemical logic will facilitate this objective. There also remains a great need to uncover currently unappreciated activities associated with this community. Revealing the full scope of microbially mediated transformations in the gut may give us newinsights into themany variable and contradictory studies regarding the effects of diet, pollutants, and drugs on human health. Microbial genes and enzymes will provide both specific targets for manipulation and diagnostic markers that can be incorporated into clinical studies and practice. Ultimately, a molecular understanding of gut microbial xenobiotic metabolism will inform personalized nutrition, toxicology risk assessment, precision medicine, and drug development.
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影响因子：
30.3
作者：
Devlin AS;Marcobal A;Dodd D;Nayfach S;Plummer N;Meyer T;Pollard KS;Sonnenburg JL;Fischbach MA
通讯作者：
Fischbach MA
影响因子：
8.6
作者：
Bodea S;Funk MA;Balskus EP;Drennan CL
通讯作者：
Drennan CL
DOI：
10.1073/pnas.1215689109
发表时间：
2012-12-26
影响因子：
11.1
作者：
Craciun, Smaranda;Balskus, Emily P.
通讯作者：
Balskus, Emily P.
影响因子：
4.3
作者：
BORZELLECA, JF;DEPUKAT, K;HALLAGAN, JB
通讯作者：
HALLAGAN, JB
DOI：
10.1073/pnas.0904489106
发表时间：
2009-08-25
影响因子：
11.1
作者：
Clayton, T. Andrew;Baker, David;Nicholson, Jeremy K.
通讯作者：
Nicholson, Jeremy K.